STUDIES ON THE EFFECTIVE REGULATION OF MATRIX METALLOPROTEINASES IN PHEUMATOID ARTHRITIS

1992年和1993年，为了建立有效调控类风湿关节炎中参与基质降解的基质金属蛋白酶（matrix metalloproteinases, MMPs）的方法，研究了人滑膜成纤维细胞中白细胞介素1 （interleukin 1, IL-1）、IL-6和前列腺素E （prostaglandin E， PGE）在MMPs生成中的确切作用。此外，还评价了吲哚美辛环加氧酶抑制剂对MMPs生成的影响。IL-6不调节人滑膜细胞中细胞外基质成分（包括透明质酸和蛋白聚糖）的代谢，以及质浆原激活剂和PGE2的产生。IL-6加速了组织金属蛋白酶抑制剂（TIMP-1）的产生，但不影响MMPs的产生。然而，在IL-1的存在下，IL-6增加了IL-1介导的MMPs的产生，表明IL-6被发现是炎症的启动子。这些结果发表在journal of Arthritis Rheumatol. 35: 1197-1201（1992）上，否定了IL-6可能是一种抗炎细胞因子的概念。在类风湿滑膜细胞中，PGE1和PGE2均抑制il -1介导的MMPs的产生。吲哚美辛和双氯芬酸环氧化酶抑制剂进一步增强了il -1诱导的MMPs的产生，这种增强被发现是由于这些抑制剂抑制内源性PGE的结果。总之，在类风湿关节炎中，IL-6和IL-1被认为是炎症促进因子。PGE2被认为是炎症介质，可作为抗炎因子抑制MMP的产生。因此，从这个角度来看，环氧化酶抑制剂可能不适合用于抗类风湿药物，因此合理的抗类风湿药物应该设计成直接抑制IL-1和MMPs的产生，和/或作为IL-1的抑制剂，如IL-1受体拮抗剂。

In 1992 and 1993, to establish the effective methods for the regulation of matrix metalloproteinases (MMPs) which participate the matrix degradation in rhuematoid arthritis, the exact roles of interleukin 1 (IL-1), IL-6 and prostaglandin E (PGE) on the production of MMPs in human synovial fibroblasts were investigated. Furthermore, effect of cyclooxygenase inhibitor of indomethacin on the MMPs production was also evaluated.IL-6 did not modulated the metabolism of extracellular matrix components including hyaluronic acid and proteoglycans, and plasmiogenactivator and PGE2 production in human synoviocytes. IL-6 accelerated the production of tissue inhibitor of metalloproteinases (TIMP-1) without affecting the MMPs production. Under presence of IL-1, however, IL-6 augmented the IL-1-mediated production of MMPs, indicating that IL-6 is found to be a promoter for the inflammation. These results have been published in the journal of Arthritis Rheumatol. 35 : 1197-1201 (1992), and denied the concept that IL-6 was likely to be an anti-inflammatory cytokine.In rheumatoid synovial cells, both PGE1 and PGE2 suppressed the IL-1-mediated production of MMPs. Cyclooxygenase inhibitor of indomethacin and diclofenac further augmented the IL-1-induced production of MMPs, and this augmentation was found to be resulted from the suppression by these inhibitors of endogenous PGE.In conclusion, in rheumatoid arthiritis IL-6 in addition to IL-1 was characterized as an inflammation promoting factor. PGE2 which is recognized as the inflammation mediator acted as an anti-inflammatory factor to suppress the MMP production. From this point of view, therefore, cyclooxygenase inhibitors might be unsuitable for anti-rheumatoid drugs, and thus reasonable anti-rheumatoid drugs should be designed to suppress directly the production of IL-1 and also MMPs, and/or to be a inhibitor for IL-1 such as the IL-1-receptor antagonist.